A nuclear factor-kappaB inhibitor BAY11-7082 inhibits interactions between human endothelial cells, T cells, and monocytes.
Costimulatory molecules play critical roles during cell-mediated immune responses. We undertook this study to determine whether CD154-CD40 interactions induced human endothelial cell (EC) activation via the nuclear factor (NF)-kappaB pathway, and whether the upregulation of monocyte-derived CD40 and CD80 is NF-kappaB pathway dependent. A CD154-expressing D1.1 cell-EC coculture with or without the NF-kappaB inhibitor BAY11-7082 was established to examine EC activation as indicated by CD62E expression. Peripheral blood mononuclear cell (PBMC)-EC cocultures were performed in the presence or absence of BAY11-7082; the expression of CD40 and CD80 on monocytes was analyzed by FACS. Allogeneic mixed lymphocyte-EC reaction (MLER) was performed to determine the inhibitory effects of BAY11-7082 to prevent lymphocyte proliferation. FACS demonstrated upregulation of EC-derived CD62E expression induced by CD154 expressing D1.1 cells. BAY11-7082 pretreated EC failed to upregulate CD62E after interaction with D1.1 cells. Monocytes upregulated CD40 and CD80 expression during PBMC-HEC interaction, and BAY11-7082 suppressed monocyte-derived CD40 and CD80 expression in a dose-dependent manner. The monocyte-derived CD86 expression was downregulated by NF-kappaB inhibitor. BAY11-7082 demonstrated inhibition of lymphocyte proliferation of allogeneic MLER. This study demonstrated that the NF-kappaB inhibitor BAY11-7082 prevented CD154-CD40 interaction-induced EC activation, suggesting that the activation of EC by T-cell-derived CD154 is via NF-kappaB pathway. The NF-kappaB inhibitor suppressed upregulation of monocytederived CD40 and CD80. Additionally, BAY11-7082 suppressed lymphocyte proliferation in response to allogeneic EC. These data indicated that NF-kappaB plays an important role in regulating costimulatory molecules in allogeneic immune responses, and strengthens the rationale for the use of NF-kappaB-directed therapy in allotransplantation.
Zhu
B
B
Department of Transplantation, Jinan City Central Hospital, Jinan, Shandong, P.R. China.
Liu
Z
Z
Wang
P
P
Wu
C
C
Xu
H
H
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D023201:CD40 Ligand / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016328:NF-kappa B; D009570:Nitriles; D011994:Recombinant Proteins; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma